The marked increase in cardiovascular disease (CVD) in patients with type 2 diabetes (T2D) demands an integrated approach to cardiometabolic disease. A major goal of the PPG is to elucidate common mechanisms in distinct cell types that contribute to cardiometabolic disease. Our PPG work has shown that obesity/insulin resistance and atherosclerosis activate a CaMKII/MK2 kinase pathway in hepatocytes (HCs) and macrophages (M?s), respectively. In HCs, this pathway disrupts insulin receptor signaling, leading to systemic insulin resistance, and also down-regulates tissue plasminogen activator (tPA), which in humans predicts higher risk of CVD. In M?s, the pathway promotes plaque progression by impairing apoptotic cell clearance (efferocytosis) and inflammation resolution. In work with Dr. Tall, we have evidence that part of the mechanism involves CaMKII-mediated suppression of LXR?. Finally, based on our PPG work with Drs. Accili and Tall, we propose that the HC pathway, by inducing hyperinsulinemia, amplifies the lesional M? pathway, leading to a pathogenic cardiometabolic feedback loop. In this context, the overall objective is to investigate the mechanisms and consequences of the CaMKII/MK2 pathways in HCs and M?s in metabolism and atherosclerosis and to explore its therapeutic potential. In Aim 1, we will investigate the role of M? CaMKII in advanced atherosclerosis and its amplification by insulin resistance. We hypothesize that the CaMKII/MK2 pathway in M?s promotes advanced atherosclerosis by impairing resolution and by down-regulating LXR?, which compromises MerTK-mediated efferocytosis. We will use WD-fed Ldlr-/- mice with myeloid-CaMKII KO, with or without other alterations, e.g., deleted myeloid LXR? with Dr. Tall. We will also feed the mice an atherogenic/diabetogenic diet to test the hypothesis that the M? CaMKII pathway is amplified by insulin resistance and that myeloid-CaMKII KO will have particular benefit in this setting. In Aim 2, we will test the hypothesis that activation of the CaMKII/MK2 pathway in HCs in obesity promotes atherosclerosis by at least two mechanisms. First, based on our PPG work with Drs. Tall and Accili, hyperinsulinemia down-regulates insulin signaling in M?s, elevates M? Ca2+i, and activates CaMKII (Aim 1). Second, we have exciting new in vivo data that the CaMKII pathway in HCs suppresses circulating tPA activity. Low tPA is a risk factor for human CVD, with relevance to T2D, but precise role in atherosclerosis is unknown. In this context, we will test the hypothesis that silencing the CaMKII pathway in HCs in the diabetic Ldlr-/- mice used in Aim 1 will lessen advanced atherosclerosis by suppressing the M? pathways outlined in Aim 1 and also by increasing tPA. Then, based on our recent publication, we will treat the diabetic Ldlr-/- mice with a specific inhibitor of the CaMKII/MK2 pathway to explore the potential therapeutic implications of our studies for cardiometabolic disease. 1